Reversing Diabetes

Laura Freeman

Published: April 8, 2015

Anath Shalev, MD (right) and a researcher in Shalev’s lab.

Could a Four Dollar Generic be the Answer?

Rogue T- cells that attack the body’s own pancreatic beta cells have long been known as the primary villains in the autoimmune process that becomes Type 1 diabetes. Several years ago, a second culprit was discovered lurking behind the scenes. Its role in contributing to beta cell death and diminished function was unmasked in research led by Anath Shalev, MD, director of UAB’s Comprehensive Diabetes Center.

“We started by looking to see which gene in human islet cells seems to be most affected by the high glucose levels that are a hallmark of diabetes,” Shalev said. “That’s what brought our attention to a strong over-expression of thioredoxin-interacting protein, or TXNIP. As we continued to investigate, we found that high levels of TXNIP destroyed beta cells through a mitochondrial death pathway, and it seems to be involved in inflammation related to some of the more serious complications of diabetes, including cardiomyopathy, retinopathy and kidney damage.”

The center’s continuing research recently identified a second critical role TXNIP plays in diabetes when it found that high levels of the protein directly block insulin production through a new pathway. It induces a microRNA, miR-204, to down-regulate the MAFA transcription factor involved in promoting transcription of the insulin gene. This offers a second new target for therapies to counteract the progression of diabetes.

The first target was reducing the overproduction of TXNIP itself. Shalev had noticed in an earlier study that a calcium channel blocker seemed to be effective in inhibiting TXNIP overproduction.

“We were able to show that Verapamil had this effect. It has been around for over 30 years and has been used extensively in hypertension and migraine headaches with minimal side effects,” Shalev said. “In both mouse studies and human islet cells, Verapamil reduced TXNIP levels.”

In fact, the response was so dramatic that when mouse models with established diabetes and blood sugars above 300 milligrams per deciliter were treated with Verapamil, the disease was eradicated.

The next thought is how well will human diabetics respond? Answering that question is the goal of a new clinical study funded by the JDRF that has just begun recruiting 52 subjects, and recruitment is expected to continue through the end of the year. To qualify, subjects must be between the ages of 19 and 45, and have been diagnosed with Type 1 diabetes within the past three months.

Fernando Ovalle, MD, director of UAB’s Comprehensive Diabetes Clinic, and co-principal investigator, will oversee all clinical aspects of the trial. Patients will be using insulin pumps and 24-hour glucose monitoring.

Shalev is optimistic, but cautions that with such different life spans, what can be achieved in a one-year study in humans compared to a one-year study in mice is hard to predict.

“We think we will see some improvement, and even a small amount of improvement in beta cell survival and function can make a significant difference,” Shalev said. “Recent research has shown that even after decades, a large number of diabetics have more surviving beta cells than we once thought possible. If we can create an environment more conducive to protecting beta cells and improving their function by inhibiting excessive TXNIP expression, we could advance the treatment of diabetes from an entirely new direction. It may also be possible to reduce the complications from damage excessive TXNIP does in other tissues.”

The ability to inhibit over expression of the gene producing the TXNIP protein would also likely have benefits for patients who have Type 2 diabetes, since high glucose levels seem to be triggering similar effects and problems from the protein.

Shalev also pointed out that two additional advantages to this approach is that reducing TXNIP doesn’t require any suppression of the immune system and Verapamil is a known drug already approved by the FDA. Its action is well understood and it is generally well tolerated. At dosages used to treat migraines, it has already been used in patients without hypertension with no significant impact on blood pressure.

“Generally, thought in the field has moved from transplants to the less invasive approach of protecting and improving the patient’s own beta cell mass and function. In our mouse studies, we’ve seen some indirect indications that it may be possible to encourage beta cell replication or even perhaps regeneration,” Shalev said. “Something seems to be going on. We haven’t been able to determine whether it’s just improvement in beta cell function, or actual regeneration, but whatever it is, the possibilities are exciting.”